Following injury fibroblasts are necessary for proper wound healing to occur. However, excessive fibroblast production of extracellular matrix (ECM) proteins in response to injury and/or fibrosis in otherwise normal tissue may alter tissue architecture so that organ function is adversely affected. Examples include the fibrosis that occurs in distant non-infarcted segments of the heart following myocardial infarction and cardiac fibrosis that develops in response to pressure overload of the heart. The understanding of basic mechanisms involved in fibrosis, however, has been limited by the absence of a good experimental model to alter fibroblast functions within the whole animal. The discoidin domain type 2 receptor (DDR2) is a receptor for fibrillar collagens that is expressed by fibroblast and fibroblast-like cells throughout the body. In the heart DDR2 is expressed solely on fibroblasts. In this proposal a tamoxifen-inducible Cre recombinase (i.e., MerCreMer) will be introduced into one of the murine DDR2 alleles by homologous recombination (i.e., knockin). Thus, MerCreMer will be expressed only in cells that also express DDR2. This DDR2-MerCreMer model can be crossed with another mouse containing any gene-of-interest flanked by loxP sites. When double-mutant progeny are treated with tamoxifen the gene-of-interest will be deleted only within the fibroblastic cells of the animal. Development of this model will allow the study of fibrosis and disease progression not only in the heart but also in other organs of the body where DDR2 is expressed. In addition, controlled removal of fibroblast gene products will allow the in vivo study of their contribution to organ development, organ homeostasis, wound healing, tissue ageing and tissue biomechanical properties. Thus, this proposal seeks to develop a model that will be useful across many disciplines of health-related research. [unreadable] [unreadable]